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Benign behavioral intervention

“Benign behavioral intervention” is described in 46.104(d)(3) as behavioral (not biomedical) “interventions in conjunction with collecting information from an adult subject through oral or written responses (including data entry) or audiovisual recording if the subject prospectively agrees to the intervention and information collection and certain conditions are met” (HHS 2017). The new exemption is for the research activities that pose little risk of harm to subjects.

The regulations at 46.104(d)(3)(ii) (HHS 2017) also adds that benign behavioral interventions are:

  • Brief in duration
  • Harmless
  • Painless
  • Not physically invasive
  • Not likely to have a significant adverse lasting effect on the subjects
  • Not likely to be offensive or embarrassing to subjects

The preamble gives the following examples of benign behavioral interventions (HHS 2017):

  • Having the subjects play an online game
  • Having the subjects solve puzzles under various noise conditions
  • Comparing test performance of test takers in quiet or noisy surroundings
  • Having subjects decide how to allocate a nominal amount of received cash between themselves and someone else

Note: The Final Rule includes three of the above examples in the regulatory language.

Broad Consent

The Final Rule presents a new concept of “broad consent” in 46.116(a) and (d), which addresses elements of consent for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. The preamble defines broad consent as “seeking prospective consent to unspecified future research” (HHS 2017). Waivers and refusals of broad consent are addressed in 46.116(e). Broad consent may be obtained only for the storage, maintenance, and secondary research uses of identifiable private information and identifiable biospecimens.

Clinical Trial

A clinical trial is a means a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes.

Conflict of Interest (COI)

The term Conflict of Interest (COI) refers to situations in which financial or non-financial considerations may compromise, or have the appearance of compromising, a researcher’s objectivity in meeting duties or responsibilities (including those associated with research activities). The potential bias that COIs may impact can affect numerous research activities including:

  • Decisions about enrollment and inclusion/exclusion criteria
  • Decisions about the choice of personnel to conduct the study
  • Recruitment and consenting of research projects
  • Vendor selection in the purchase of equipment and other supplies
  • Data collection, analysis, and interpretation
  • Sharing of research results
  • Choice of research design and statistical methods

Bias, or the appearance thereof, can be extremely detrimental to research integrity and erode the public trust in the research enterprise if not addressed in a transparent manner.

Transparency, through disclosure and management of Conflicts of Interest, is critical to the integrity of the research, advancement of science, and the protection of human subjects.

Examples of Informed Consent Form Language with COI Disclosure

  • The researcher, Dr. Michael Shoes, owns stocks in the company that is paying for the research.
  • The researcher, Ms. Anne Therapist, is recruiting participants from a professional organization to which she belongs and whose individual members she may know.
  • The researcher, Mr. Art Student, is conducting research at his internship site with clients with whom he may have interacted in both professional and personal capacities.
Inherent Controls to Minimize COI
Blinding Researcher to Treatment Arm A researcher with a COI who is blinded to treatment arm(s) would not likely be able to introduce bias into the research.
Independent Data Analysis

Use of an outside third party to conduct data analysis, so the researcher with the COI would not be able to introduce bias into the data analysis.

In multi-site clinical trials, data analysis is often conduced by a contract research organization of the sponsor rather than by local researchers who may have financial COIs related to the study.

Limiting Subject Enrollment at Local Site If a researcher at the organization disclosed a COI related to a multi-center clinical trial enrolling 1,500 subjects nationwide but only enrolling two subjects at the site locally, the fact that less than one percent of subjects will be enrolled at the local site minimizes the risk that the researcher could bias the research.


The definition of “deception” is not included in the definitions section, but it is specified in 46.104(d)(3)(iii) and the Final Rule’s preamble, which states “authorized deception would be prospective agreement by the subject to participate in research where the subject is informed that he or she will be unaware of or misled regarding the nature or purposes of the research” (HHS 2017).

Generalizable Knowledge

The term “generalizable knowledge” remains undefined and unaddressed in the Final Rule. Each institution should define, in its standard operating procedures (SOPs) or other institutional documentation, what standard is used. Typically, this involves some variation of the thought that the results are intended/expected to be applied to a larger population beyond the site of data collection or the population studied.

High Risk

High risk means that participation in the research might include potential danger or more severe levels of distress.

Human Subject

A human subject is a living individual about whom an investigator (whether professional or student) is conducting research that:

  • Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
  • Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

Identifiable Private Information

Identifiable private information is private information for which the identity of the subject is or may readily be ascertained by the investigator or associated with the information. An identifiable biospecimen is a biospecimen for which the identity of the subject is or may readily be ascertained by the investigator or associated with the biospecimen.

Institutional Review Board (IRB) Approval

Institutional Review Board (IRB) approval means the determination of the IRB that the research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and federal requirements.


Interaction includes communication or interpersonal contact between investigator and subject.


Intervention includes both physical procedures by which information or biospecimens are gathered (e.g., venipuncture) and manipulations of the subject or the subject’s environment that are performed for research purposes.

Key Information

There were many changes to the informed consent process and documentation, and one undefined, but important, regulatory term added is “key information.” The Final Rule (HHS 2017) states that key information must receive priority by appearing at the beginning of the consent form and be presented first in the consent discussion. According to the Final Rule’s preamble (HHS 2017), a brief description of five elements at the beginning of the consent form, and informed consent process, would encompass the required key information:

  1. The fact that consent is being sought for research and that participation is voluntary;
  2. The purpose of the research, expected duration of the prospective subject’s participation, and procedures to be followed in the research;
  3. The reasonably, foreseeable risks or discomforts to the prospective subject;
  4. The benefits to the prospective subject or others that may reasonably be expected from the research; and
  5. Appropriate alternative procedures of courses of treatment, if any, that might be advantageous to the prospective subject.

Legally Authorized Representative

The definition of legally authorized representative now adds specific authorization to use institutional policy when there is no applicable law (state statute or regulation, case law, or an opinion of a state attorney general) that addresses this issue. This change is intended to bring consistency to the consent process. When there is not an applicable law, this change allows policies that are in place in a non-research context (for example, clinical context) to be used to determine who may serve as a legally authorized representative at an institution.

Limited IRB Review

Limited IRB review is a condition for exemption of the research activities under:

  • 104(d)(2)(iii):Identifiable and sensitive educational tests, survey procedures, interview procedures, or observation of public behavior;
  • 104(d)(3)(i)(c):Identifiable and sensitive benign behavioral interventions;
  • 104(d)(8):Secondary research use; and
  • 104(d)(7):Storage or maintenance for secondary research for which broad consent is required

The Final Rule’s preamble (HHS 2017) states that, for the first three of these exemptions, a limited IRB review is making and documenting the determination required by 46.111(a)(7) “to ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens” in the proposed research.

A new limited IRB review criterion at 46.111(a)(8) adds additional broad consent determinations for approval of activities that store and/or maintain private information or identifiable biospecimens for secondary research use under exemption 46.104(d)(7). This new criterion states that for storage and maintenance, “the IRB need not make the determinations at paragraphs (a)(1) through (7) of this section” (HHS 2017).

Therefore, limited IRB review uses a single criterion, specifically either46.111(a)(7) or 46.111(a)(8).

To clarify that IRBs have the authority needed to conduct limited IRB review, the Final Rule modifies the IRB authority listed in 46.109 (to approve, require modifications in, or disapprove research) by adding “including exempt research activities under 46.104 for which limited IRB review is a condition of exemption” (HHS 2017).

Minimal Risk

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Moderate Risk

Moderate risk means that participation in the research may induce distress, significant fatigue, or need for extensive debriefing or explanation due to some deception involved in the research.


The word “practicably,” which appears in the informed consent waiver and alteration sections, is intentionally left undefined. The preamble notes that a SACHRP recommendation with regard to the obtaining of consent was that “this requirement be interpreted to mean that it would be impracticable to perform the research [if consent was required], not impracticable to obtain consent due to financial or administrative burdens, without the waiver or alteration” (HHS 2017).

Private Information

Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information that has been provided for specific purposes by an individual and that the individual can reasonably expect will not be made public (e.g., a medical record).

Public Health Authority

Public health authority means an agency or authority of the United States, a state, a territory, a political subdivision of a state or territory, an Indian tribe, or a foreign government, or a person or entity acting under a grant of authority from or contract with such public agency, including the employees or agents of such public agency or its contractors or persons or entities to whom it has granted authority, that is responsible for public health matters as part of its official mandate.


Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities. For purposes of this part, the following activities are deemed not to be research:

  1. Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), including the collection and use of information, that focus directly on the specific individuals about whom the information is collected.
  2. Public health surveillance activities, including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products). Such activities include those associated with providing timely situational awareness and priority setting during the course of an event or crisis that threatens public health (including natural or man-made disasters).
  3. Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes.
  4. Authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions.

Secondary Research Use

Secondary Research Use is not defined in the regulations, but the Final Rule’s preamble (HHS 2017) states it is “re-using [for research purposes] identifiable and non-identifiable information and biospecimens that are collected for some other ‘primary’ or ‘initial’ activity” (such as from research studies other than the proposed research study).

The information or biospecimens that are used for secondary research would generally be found by the investigator in the following: Records, Information Systems, Archives, Databanks (in the case of information), Tissue repositories (such as a hospital’s department for storing clinical pathology specimens or the excess portion of removed tissue or blood that was drawn for clinical purposes)

Single IRB (SIRB) Review and Cooperative Research

“Single IRB review” is also not specifically defined in the Final Rule. However, 46.114 (HHS 2017) adds a requirement for institutions located in the U.S., that are engaged in federal cooperative research, to rely upon approval by a sIRB for the portion of research that is conducted in the U.S. “Cooperative research” is explained within the regulation at 46.114 as research “involving more than one institution” (in other words, essentially all federal multi-site research). Single IRB is synonymous with “reviewing IRB” and “IRB of record.” All other IRBs are “relying IRBs.” Further guidance is expected from the Office for Human Research Protections (OHRP).

Vulnerable (to coercion or undue influence)

The term “vulnerable” is not included in the definitions section, but the wording surrounding it has been updated in both 46.107 (IRB membership requirements) and 46.111 (Criteria for approval of research). The Final Rule uses the term “individuals with impaired decision-making ability”. The Final Rule’s preamble (HHS 2017) states that the possibility of coercion or undue influence could affect the ability to make an informed decision about participating in research. Therefore, IRBs should consider vulnerability of the subjects in research studies “as a function of the possibility of coercion or undue influence” (HHS 2017). The preamble states that this type of vulnerability alone should be the IRB focus of concern in determinations about vulnerable populations. The preamble also notes that the assessment of the equitable selection of subjects, as noted at 46.111(a)(3), should include factors like societal marginalization or discrimination. Likewise, the preamble discusses that the criterion at 46.111(a)(1) includes risks of harm that some might term “vulnerabilities,” which are not covered by the regulatory term.

Written or in Writing

Written or in writing for purposes of this part, refers to writing on a tangible medium (e.g., paper) or in an electronic format.